December 29 2008 post. A blog reader/myeloma list friend (thank you!) sent me the link to a newly published study on genistein and multiple myeloma: http://tinyurl.com/a3qezp
Sherlock is abroad for the holidays, so I can’t get my hands on the full study until she returns, but the abstract gives us enough information for a preliminary report: genistein down-regulates NF-kappaB and related gene products…bcl-2 and bcl-x (well, well…well!) and others. But the main point is that genistein kills human myeloma cells, thus providing the molecular basis for the treatment of myeloma patients with this pharmacologically safe agent.
I had paid no serious attention to genistein because of the well-known problem of genetically modified soy…oh, right, because genistein derives mainly from soybeans, though small quantities can be found in other legumes, such as chickpeas. But from now on I will be keeping closer tabs on it. And perhaps eating more chickpeas…
This morning I bumped into another reason to keep an eye on genistein. A 2002 abstract (see: http://tinyurl.com/86ednx) discussed lab tests showing that genistein stimulates osteoblasts and inhibits osteoclasts; that is, it stimulates bone formation and prevents bone destruction. But these results had not been verified on human subjects…until 2002, that is.
That is when Italian researchers performed a randomized double-blind placebo-controlled study to evaluate and compare with hormone-replacement therapy (HRT) the effect of the phytoestrogen genistein on bone metabolism and bone mineral density (BMD) in postmenopausal women.
You can read many more details in the abstract, but the point is that This study confirms the genistein-positive effects on bone loss already observed in the experimental models of osteoporosis and indicates that the phytoestrogen [genistein, that is] reduces bone resorption and increases bone formation in postmenopausal women.
Excellent news for us myeloma folks…but before getting too excited about genistein and testing it on ourselves, my advice is to do more research into any possible risks and side effects (allergic reactions to soy and so on). I am definitely not in the genistein camp yet…but I am still reading, even though my task is rendered more difficult by the obnoxious presence of blatantly biased (one way or the other) websites. We need to find objective, more reliable sources…
Update, January 7 2009 post. A blogging friend sent me the full genistein study (thanks!!!) recently published in “Phytotherapy Research” (abstract: http://tinyurl.com/7wwnku), a study that I mentioned in my December 29th post. It starts out with the usual dismal information about multiple myeloma, which is a B-cell malignancy characterized by the latent accumulation in bone marrow of secretory plasma cells with a low proliferative index and an extended life span and accounts for 1% of all cancers and more than 10% of all blood cancers…oh, and it remains incurable…
There follows a description of what happens when the transcription factor NF-kappaB gets constitutively activated (that simply means that it is activated all the time)…this is not good, as far as we myeloma folks are concerned, since it means that our myeloma cells are protected from apoptosis (=from kicking the bucket). Reading on…blablablabla…okay, the upshot: NF-kappaB is an important target for myeloma treatment. So far, we have learned nothing new.
The research team chose to test genistein, a predominant isoflavone found in soybeans, which has been shown to inhibit the growth of various cancer cells in vitro and in vivo without toxicity to normal cells. Genistein suppresses NF-kappaB and many of the genes that it regulates. And humans can consume it safely, so they say.
Results. The team tested two different myeloma cell lines that expressed a hyperactive NF-kappaB. The cells were treated with different amounts of genistein and doxorubicin. A very small amount of genistein was sufficient to suppress the activation of NF-kappaB. It also worked synergistically with doxorubicin, leading to greater antitumor activity in vitro. Good.
For the more technically-oriented, genistein also inhibited Akt phosphorylation (when this happens, NF-kappaB doesn’t travel to the nucleus, which is a GOOD thing, take my word for it) and down-regulated ICAM-1, cyclin D, bcl-2 and bcl-xL (=four wicked genes).
Okay, but does genistein kill myeloma cells? Yes. How? Well, The precise molecular mechanism is not clear, the researchers admit. But wowie zowie, check this out: like curcumin, zerumbone and cyclopamine, genistein inhibits the Notch-1 pathway…does anyone remember what that pathway is? Right, it has to do with STEM cells…well, this might tip the balance in genistein’s favour, as far as I am concerned…yes, this is good news indeedie! I am so glad I read the full study!
Thanks to my big-hearted blogging friend, I have in my possession the 2006 genistein-Notch full study, which is next on my reading list…in the meantime, scribble scribble, a mental note: make more chickpea curries for dinner…
Update (January 9 2009): A blog reader sent me this abstract on the synergistic effect on pancreatic cancer cells of gossypol and genistein: http://tinyurl.com/7r7ap4 Too bad that gossypol is a bit on the toxic side (see my Gossypol analogue Page for more info)…
Update, January 9 2009 post: Yesterday I went through the 2006 “International Journal of Cancer” study (abstract: http://tinyurl.com/7eady3), which discusses how genistein affects the transcription factor NF-kappaB and the Notch-1 signalling pathway in pancreatic cancer cells.
[Note 1: Notch signalling is crucial for the growth and survival of multiple myeloma cells, not just pancreatic cancer cells…see, for instance, these two “Blood” 2004 abstracts: http://tinyurl.com/9p7k5e and http://tinyurl.com/7f9vzw. So this discussion is relevant to us myeloma folks, too.]
The abstract informs us that Notch signalling helps maintain the balance between cell proliferation, differentiation and apoptosis, and thereby may contribute to the development of pancreatic cancer…this process is, however, blocked by genistein. And, by inhibiting Notch-1, genistein also blocks NF-kappaB, which mediates survival signals that inhibit apoptosis and promote cancer cell growth. This process also affects the genes controlled by NF-kappaB, as we will see in a sec.
The cancer cells have no way out…except death.
[Note 2: the implications of inhibiting the Notch/NF-kappaB signalling process gave another push to my idea of gathering in one place (say, an Excel spreadsheet) all the data I have collected in the past year or so…if only I had more free time, had a scientifically-oriented brain, and were more organized…eh. Well, my rambling all over the place will simply have to do for now. But I have to admit that even I get overwhelmed by all the info contained in my own blog!!! If I could condense it somehow…]
The full study begins with the usual cancer statistics…in this case, of course, those concerning pancreatic cancer, which has the worst prognosis among all major cancers. Apparently, though, people whose diets are high in soy are less likely to get this type of cancer, suggesting that a high intake of soy products may protect people against pancreatic cancer.
Basically, as anticipated in the abstract, the study demonstrates that the inhibition of Notch-1 blocks NF-kappaB, at least in part. And this process also hinders genes that are regulated by NF-kappaB, such as COX-2, cyclin D1, MMP-9, Bcl-2, Bcl-xL and survivin. Well, well, we meet again…these are all genes implicated in the survival and merrymaking of myeloma cells, so this is a very important point.
In conclusion, the study demonstrates that the administration of genistein leads to the death of pancreatic cancer cells. The researchers speculate that one possible mechanism by which genistein induces apoptosis is due to down-regulation of Notch-1, a gene that is abnormally activated in many human malignancies and keeps pancreatic cancer cells alive and well, as it does with other types of cancer cells (erythroleukemia and cervical cancer are mentioned here).
And, as we know from my December 29 post, it also kills myeloma cells AND increases bone formation…
Toxicity issues. I was actually somewhat reassured after perusing a report carried out by the National Toxicology Program (U.S. Dept of Health and Human Services) in 2006, see http://tinyurl.com/9voc22 Incidentally, it answers Chris’ question concerning chickpeas. Even though the main source of genistein is soy, much smaller amounts can also be found in Lentils, peas, kidney beans, peanuts, chickpeas, broccoli, cauliflower, and barley meal. The report concludes that genistein is safe for human (adult) consumption. In order to reach possibly harmful levels of genistein, we would have to swallow huge quantities of the stuff, more than 35 mg/kg a day. Yep, that’s a lot. In any event, the main potential toxicity has to do with reproductive issues, which is not a concern for me.
I also took a look at a more recent (=2008) NTP report (see: http://tinyurl.com/7z3gnd) that confirms that although genistein did show adverse effects with dietary exposures of 100 or 500 ppm, there were no clear adverse effects on the reproductive or developmental parameters measured at genistein concentrations ranging from less than 1 ppm (control diet) to 100 ppm, a range of doses producing serum concentrations achievable from the phytoestrogen content of human diets.
Well, the more I read, the more I am tempted to try genistein (only from a certified non-GMO source), but I have other things to test first…in the meantime, I will (try to) keep an eye on this substance, too…